Leishmaniosis is a neglected tropical disease, an illness that kills up to 30,000 people yearly. Existing drugs have serious drawbacks in terms of safety, resistance, stability, difficulty of administration and cost. Thus, there is a need for new treatments. The aminopyrazole class of compounds originally from Pfizer has shown promising early profiles for the treatment of both visceral and cutaneous leishmaniosis. [1] In the frame of an Open Synthesis Network (OSN) between the University of Geneva and the Drugs for Neglected Diseases initiative (DNDi), we aimed at synthetizing new aminopyrazole analogues for early stage discovery for new treatments for leishmaniosis.

In order to explore the aminopyrazole chemotypes, we set up a 5-steps synthesis to obtain theoretically 42 different products. The two key reactions are reductive amination and peptidic coupling during which structural diversification occurs. Biological activity has been assessed on Leishmania infantum and cytotoxicity on human and murine fibroblasts. In 2018, this multi-steps synthesis led to 14 new compounds that have been fully characterized by HRMS, ¹H-NMR, ¹³C-NMR, IR and HPLC. All final compounds have been tested in vitro for both efficacy and toxicity. Two of them have shown high potency against Leishmania infantum (IC₅₀ 0.3 and 1.5 microM) and a selectivity index (CC₅₀/IC₅₀) ranging from 27 to 213. The open source nature of this project aimed at deepening the learning of laboratory work in the context of students R&D practical work. The collaborative spirit of the students has led to the successful synthesis output and the development of a scientific rigor of work, which includes the preparation and the follow-up plans of experiment. The promising anti-leishmaniosis activity has clearly indicated an SAR and the possibility of further exploring the current chemotype to improve compounds efficacy and selectivity. The two most potent compounds have undergone in vitro ADME studies and have shown metabolism issue. In this context, a new set of 24 compounds was designed for praticle work in 2019…

[1] Mowbray C. E. et al. J. Med. Chem. 2015; 58 (24): 9615-9624.